trans

406 DRUG RESISTANCE
clinical evidence showing the superior efficacy
of amodiaquine even in areas with a high incidence
of chloroquine-resistant parasites. Taking
all the available evidence it would appear
that although amodiaquine and its desethyl
metabolite are substrates for the chloroquineresistance
mechanism, the mechanism fails to
limit drug access to heme to an extent sufficient
to be therapeutically relevant. It will be interesting
to see if additional mutations in PfCRT
and/or changes in alternative resistance genes
will compromise the clinical efficacy of amodiaquine
as its use increases in chloroquineresistant
areas.
The quinoline and phenanthrene methanols
The quinoline methanols mefloquine and quinine
and the phenanthrene methanol halofantrine
share structural similarities (Figure
16.2) and all three drugs require the generation
of intraparasitic heme in order to exert
their full anti-malarial action. Although these
three drugs are often grouped together, there
are clear differences between quinine, mefloquine
and halofantrine in terms of the speed
of resistance development and cross-resistance
pattern. Clinical resistance to quinine has been
very slow to develop, although it is now recognized
that many parasite isolates from SE Asia
have reduced susceptibility to quinine which
is of clinical relevance. In Africa most parasites
appear to have retained sensitivity to quinine.
In contrast to quinine, the development of
clinical resistance to mefloquine was very rapid,
occurring within a few years of the drug’s
introduction into SE Asia. In fact the loss of
effectiveness was so profound that the recommended
dosage regimen was doubled and still
resistance was seen to develop. This is a situation
that has only been arrested by the widespread
use of mefloquine in combination with
an artemisinin derivative. There are a number
of reports showing clear cross-resistance
between quinine, mefloquine and halofantrine.
Drug sensitivity correlates with drug accumulation,
and there is often an inverse relationship
between sensitivity to these drugs and
sensitivity to the 4-aminoquinolines. Interestingly,
quinine-resistant parasites often show a
verapamil effect. This has been reported once
with mefloquine but never with halofantrine
although there is some evidence that resistance
to these drugs can be selectively reversed to
a degree by a more limited number of agents,
including penfuridol.
Support for the role of pfmdr1 in resistance
to the quinoline and phenanthrene methanols
is certainly greater than that for the 4-aminoquinolines,
but again the association is far
from universal. Overexpression of pfmdr1 has
been associated with resistance (or reduced
susceptibility) to these drugs in some field isolates
of P. falciparum. Similarly, laboratory selection
for mefloquine resistance under drug
pressure, with a concomitant loss in susceptibility
to quinine and halofantrine, has been
associated with overexpression of pfmdr1
(Figure 16.3). The link between sequence
polymorphisms in pfmdr1 and resistance is
less clear. Extensive analysis of field isolates
has failed to show any consistent relationship
between mutations in pfmdr1 and drug susceptibility.
However genetic transformation studies
in which the wild-type sequence of pfmdr1 was
replaced with three of the 7G8 mutations was
associated with a reduced susceptibility to quinine
and an enhanced susceptibility to mefloquine
and halofantrine. Replacement of these
mutations with wild-type sequence resulted
in the reverse patterns of drug sensitivity, i.e.
reduced susceptibility to mefloquine and halofantrine
and increased sensitivity to quinine.
One possible explanation for these observations
would be that all three drugs are substrates
for Pgh1, hence overexpression reduces drug
MEDICAL APPLICATIONS